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Peer-reviewedCC BYMicrobial cell factories

Multi-parameter optimization of recombinant protein secretion in Bacillus subtilis: a review.

  • Askar Kholikov1,2
  • Khushnut Vokhidov3
  • Barno Alimova3
  • Ozodakhon Pulatova3
  • Yulong Zhang4,5
  • Shihui Yang6
  • Guimin Zhang7
  • Yihua Chen4,5
  • Akhmadzhan Makhsumkhanov8
8 affiliations
  1. 1Institute of Microbiology, Academy of Sciences of the Republic of Uzbekistan, Tashkent, 100128, Uzbekistan. [email protected].
  2. 2Institute of Biochemistry, Heinrich-Heine University Düsseldorf, 40225, Düsseldorf, Germany. [email protected].
  3. 3Institute of Microbiology, Academy of Sciences of the Republic of Uzbekistan, Tashkent, 100128, Uzbekistan.
  4. 4Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
  5. 5University of Chinese Academy of Sciences, Beijing, 100049, China.
  6. 6State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, 430062, China.
  7. 7State Key Laboratory of Green Biomanufacturing, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
  8. 8Institute of Microbiology, Academy of Sciences of the Republic of Uzbekistan, Tashkent, 100128, Uzbekistan. [email protected].
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Abstract

Bacillus subtilis is widely recognized as one of the most robust and versatile hosts for recombinant protein production. This review provides a comprehensive overview of the protein secretion pathway in B. subtilis, detailing its mechanistic basis and key limiting steps. We discuss the structural features of signal peptides (SPs) that govern efficient translocation and highlight recent advances in de novo promoter and signal peptide engineering. A particular focus is placed on the integration of artificial intelligence (AI) to predict and design optimal genetic elements. Drawing on findings from combinatorial and multi-parameter studies, we propose that future engineering strategies should move beyond maximizing individual parameters. Instead, achieving a dynamic balance across transcriptional, translational and secretion layers is essential to sustain high productivity while minimizing cellular secretion stress. This review offers a roadmap for systems-level engineering of B. subtilis as a next-generation protein production platform.

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Cite

BibTeXRIS
BibTeX
@article{kholikov2026multiparameter,
  title = {{Multi-parameter optimization of recombinant protein secretion in Bacillus subtilis: a review.}},
  author = {Askar Kholikov and Khushnut Vokhidov and Barno Alimova and Ozodakhon Pulatova and Yulong Zhang and Shihui Yang and Guimin Zhang and Yihua Chen and Akhmadzhan Makhsumkhanov},
  journal = {Microbial cell factories},
  year = {2026},
  month = oct,
  doi = {10.1186/s12934-026-03155-y},
  url = {https://europepmc.org/article/MED/42907859},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Multi-parameter optimization of recombinant protein secretion in Bacillus subtilis: a review.
AU  - Askar Kholikov
AU  - Khushnut Vokhidov
AU  - Barno Alimova
AU  - Ozodakhon Pulatova
AU  - Yulong Zhang
AU  - Shihui Yang
AU  - Guimin Zhang
AU  - Yihua Chen
AU  - Akhmadzhan Makhsumkhanov
PY  - 2026
DA  - 2026/10/17
JO  - Microbial cell factories
DO  - 10.1186/s12934-026-03155-y
UR  - https://europepmc.org/article/MED/42907859
AB  - Bacillus subtilis is widely recognized as one of the most robust and versatile hosts for recombinant protein production. This review provides a comprehensive overview of the protein secretion pathway in B. subtilis, detailing its mechanistic basis and key limiting steps. We discuss the structural features of signal peptides (SPs) that govern efficient translocation and highlight recent advances in de novo promoter and signal peptide engineering. A particular focus is placed on the integration of artificial intelligence (AI) to predict and design optimal genetic elements. Drawing on findings from combinatorial and multi-parameter studies, we propose that future engineering strategies should move beyond maximizing individual parameters. Instead, achieving a dynamic balance across transcriptional, translational and secretion layers is essential to sustain high productivity while minimizing cellular secretion stress. This review offers a roadmap for systems-level engineering of B. subtilis as a next-generation protein production platform.
SN  - 1475-2859
ER  -